Acylphenylurea derivatives, a process for their preparation and their use as pharmaceuticals

ABSTRACT

The invention is directed to acylphenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.  
     Compounds of the formula I  
                 
 
     in which the radicals have the stated meanings, and their physiologically tolerated salts and a process for their preparation are described. The compounds are suitable, for example, for treating type 11 diabetes.

[0001] This application claims priority benefit of Federal Republic ofGermany Application 10028175.3-42, filed Jun. 9, 2000, and FederalRepublic of Germany Application 10116768.7 filed Apr. 4, 2001, both ofwhich are incorporated by reference.

[0002] The invention is directed to acylphenylurea derivatives, theirphysiologically tolerated salts, and their physiologically functionalderivatives.

[0003] Acylphenylurea derivatives have already been described asinsecticides (EP 0 136 745, Ii EP 0 167 197, DE 29 26 480, J. Agric.Food Chem. 1999, 47, 3116-3424, which are incorporated by reference).

[0004] In one embodiment, the invention provides compounds that displaya blood glucose-lowering effect, which can be exploited therapeutically.

[0005] These include compounds of the formula (I)

[0006] in which

[0007] A is phenyl, naphthyl, it being possible for the phenyl ornaphthyl radical to be substituted up to three times by: F, Cl, Br, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂-NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO(C₁-C₇)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH_(2,)(CO-C₆)-alkylene-NH(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-Alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, it being possiblefor the phenyl ring to be substituted up to twice by F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl orCONH₂;

[0008] R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(Cl-C₆)-alkyl;

[0009] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (Cl-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]2, CONH(C₃-C₇)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl,or NH—SO₂-phenyl, it being possible for the phenyl ring to besubstituted up to twice by F, Cl, CN, OH, (C₁-C₆)-Alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl or CONH₂;

[0010] X is O or S;

[0011] R7 is (C₁-C₁₀)-alkylene-COOH,(C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-CONH₂,(C₁-C₁₀)-alkylene-CONH-(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON-[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]2,or (C₁-C₁₀)-alkylene-B;

[0012] B is (C₃-C₇)-cycloalkyl, pyrrolyl, Imidazolyi, thiazolyl,azetidinyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl,pyridyl-methyl or furyl, in which cycloalkyl, phenyl, pyrrolyl,imidazolyl, thiazolyl, azetidinyl, thienylmethyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl or furyl may in each case besubstituted up to twice by Cl, F, CN, CF₃, OCF₃, COOH,COO—(C₁-C₆)-alkyl, CONH₂, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂,(C₁-C₆)-alkyl, OH, or O—(C₁-C₆)-alkyl;

[0013] and their physiologically tolerated salts thereof, except thecompounds of the formula:

[0014] and compounds of the formula (I) in which the radicals are, atthe same time:

[0015] A phenyl;

[0016] X is O;

[0017] R1 H;

[0018] R7 —(C₁-C₄)-alkyl-B;

[0019] B (C₃-C₇)-cycloalkyl, or a heteroaryl.

[0020] Compounds of the formula (I) can include those in which

[0021] A is phenyl, naphthyl, it being possible for the phenyl ornaphthyl radical to be substituted up to three times by F, Cl, Br, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁C₆)-alkyl, S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl,SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl,(C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, it being possiblefor the phenyl ring to be substituted up to twice by F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl orCONH₂;

[0022] R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl;

[0023] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, orNH—CO-phenyl, NH—SO₂-phenyl, it being possible for the phenyl ring to besubstituted up to twice by F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl or CONH₂;

[0024] X is O or S;

[0025] R7 is (C₁-C₁₀)-alkylene-COOH, (C₆-C₁)-alkylene-COO—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CONH₂, (C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B;

[0026] B is (C₃-C₇)-cycloalkyl, pyrrolyl, imidazolyl, thiazolyl,azetidinyl, thienyl-methyl, piperidinyl, pyrrolidinyl, morpholinyl,pyridyl-methyl or furyl, in which cycloalkyl, phenyl, pyrrolyl,imidazolyl, thiazolyl, azetidinyl, thienyl, piperidinyl, pyrrolidinyl,morpholinyl, pyridyl or furyl may in each case be substituted up totwice by Cl, F, CN, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, CONH₂,CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, OH, orO—(C₁-C₆)-alkyl and their physiologically tolerated salts thereof,

[0027] except the compounds of the formula

[0028] and compounds of the formula (I) in which the radicals are, atthe same time:

[0029] A phenyl;

[0030] X O

[0031] R1 H;

[0032] R7 —(C₁-C₄)-alkyl-B;

[0033] B (C₃-C₇)-cycloalkyl, or heteroaryl.

[0034] Further examples of compounds of the formula (I) are those inwhich

[0035] A is phenyl, it being possible for the phenyl radical to besubstituted up to twice by F, Cl, Br, or O—(C₁-C₆)-alkyl;

[0036] R1, R2 are, independently of one another,H, (C₁-C₆)-alkyl, orCO—(C₁-C₆)-alkyl;

[0037] R3, R4, R5, R6 are, independently of one another, H, Cl, F,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, or —COO—(C₁-C₆)-alkyl;

[0038] X is O;

[0039] R7 is (C₁-C₁₀)-alkylene-COOH,(C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl, or (C₁-C₁₀)-alkylene-CONH₂;

[0040] and their physiologically tolerated salts thereof, except thecompounds of the formula:

[0041] In another embodiment, the invention relates to the use ofcompounds of the formula (I)

[0042] in which

[0043] A is phenyl, naphthyl, it being possible for the phenyl ornaphthyl radical to be substituted up to three times by F, Cl, Br, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH(C₁-C₆)-alkyl, (C₀-C₆)-aIkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, it being possiblefor the phenyl ring to be substituted up to twice by F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl orCONH₂;

[0044] R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl;

[0045] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl,or NH—SO₂-phenyl, it being possible for the phenyl ring to besubstituted up to twice by F, Cl, CN, OH, (C₁-C₆)-Alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl or CONH₂;

[0046] X is O or S;

[0047] R7 is (C₁-C₁₀)-alkylene-COOH,(C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-CONH₂,(C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B;

[0048] B is (C₃-C₇)-cycloalkyl, phenyl, pyrrolyl, Imidazolyl, thiazolyl,azetidinyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl orfuryl, in which cycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl,azetidinyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl orfuryl may in each case be substituted up to twice by Cl, F, CN, CF₃,OCF₃, COOH, COO—(C₁-C₆)-alkyl, CONH₂, CONH—(C₁-C₆)-alkyl,CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, OH, or O—(C₁-C₆)-alkyl;

[0049] and their physiologically tolerated salts thereof, for producinga medicine for lowering the blood glucose level and treating type 11diabetes.

[0050] In another embodiment, the invention relates to compounds of theformula (I) in the form of their racemates, racemic mixtures and pureenantiomers, and to their diastereomers and mixtures thereof.

[0051] The alkyl radicals in the substituents RI, R2, R3, R4, R5, R6,R7, A and B may be both straight-chain and branched.

[0052] Pharmaceutically acceptable salts are particularly suitable formedical applications because of their greater solubility in watercompared with the initial or basic compounds. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as, for example, hydrochloric acid,hydrobromic, phosphoric, metaphosphoric, nitric, sulfamic and sulfuricacids, and organic acids such as, for example, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.Suitable pharmaceutically acceptable basic salts are ammonium salts,alkali metal salts (such as sodium and potassium salts) and alkalineearth metal salts (such as magnesium and calcium salts).

[0053] Salts with pharmaceutically unacceptable anions such as, forexample, trifluoroacetate, likewise belong within the framework of theinvention as useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or use in nontherapeutic, forexample in vitro, applications.

[0054] The term “physiologically functional derivative” used hereinrefers to any physiologically tolerated derivative of a compound of theformula (I) of the invention, for example an ester, which onadministration to a mammal such as, for example, a human is able to form(directly or indirectly) a compound of the formula (I) or an activemetabolite thereof.

[0055] Physiologically functional derivatives include prodrugs of thecompounds of the invention, as described, for example, in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61, the relevant disclosure ofwhich is herein incorporated by reference. Such prodrugs can bemetabolized in vivo producing a compound of the invention. Theseprodrugs may themselves be active or not.

[0056] The compounds of the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of ithe compounds of theinvention belong within the framework of the invention and are a furtheraspect of the invention.

[0057] All references to “compound(s) of formula (I)” hereinafter referto compound(s) of the Iformula (I) as described above, and their salts,solvates and physiologically functional derivatives as described herein.

[0058] The amount of a compound of formula (I) that can achieve thedesired biological effect 20 depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from about 0.3 mg to about 100 mg (typicallyfrom about 3 mg to about 50 mg) per day and per kilogram of bodyweight,for example about 3-10 mg/kg/day. An intravenous dose may be, forexample, in the range from about 0.3 mg to about 1.0 mg/kg, which cansuitably be administered as infusion of about 10 ng to about 100 ng perkilogram and per minute. Suitable infusion solutions for these purposesmay contain, for example, from about 0.1 ng to about 10 mg, typicallyfrom about 1 ng to about 10 mg, per milliliter. Single doses maycontain, for example, from about 1 mg to about 10 g of the activeingredient. Thus, ampoules for injections may contain, for example, fromabout 1 mg to about 100 mg, and single-dose formulations, which can beadministered orally, such as, for example, capsules or tablets, maycontain, for example, from about 1.0 to about 1000 mg, typically fromabout 10 to about 600 mg. For the therapy of the abovementionedconditions, the compounds of formula (I) may be used as the compounditself, but they are typically in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful to the patient's health. Thecarrier may be a solid or a liquid or both, and is typically formulatedwith the compound as a single dose, for example as a tablet, which maycontain from about 0.05% to about 95% by weight of the activeingredient. Other pharmaceutically active substances may likewise bepresent in the pharmaceutical composition, including other compounds offormula (I). The pharmaceutical compositions of the invention can beproduced by one of the known pharmaceutical methods, which essentiallyconsist of mixing the ingredients with pharmacologically acceptablecarriers and/or excipients.

[0059] Pharmaceutical compositions of the invention are those suitablefor oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case, on the nature andseverity of the condition to be treated, and on the nature of thecompound of formula (I) used in each case. Coated formulations andcoated slow-release formulations also belong within the framework of theinvention, as well as acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellular acetate,phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

[0060] Suitable pharmaceutical compounds for oral administration may bein the form of several units such as, for example, capsules, wafers,suckable tablets or tablets, each of which contains a defined amount ofthe compound of formula (I); as powders or granules, as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method that includes a step inwhich the active Iingredient and the carrier, (which may consist of oneor more additional ingredients) are brought into contact. Thecompositions are generally produced by uniform and homogeneous mixing ofthe active ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, with one or more additional ingredients when appropriate.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one ormore surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, in powder form andmoistened, with an inert liquid diluent in a suitable machine.

[0061] Pharmaceutical compositions which are suitable for peroral(sublingual) administration comprise suckable tablets, which contain acompound of formula (I) with a flavoring, normally sucrose and gumarabic or tragacanth, and pastilles, which comprise the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

[0062] The pharmaceutical compositions suitable for parenteraladministration comprise aqueous preparations of a compound of formula(I), these preparations can be sterile iand/or isotonic with the bloodof the intended recipient. These preparations can be administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from about 0.1 to about5% by weight of the active compound.

[0063] Pharmaceutical compositions suitable for rectal administrationare typically in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0064] Pharmaceutical compositions suitable for topical use on the skinare typically in the form of ointment, creme, lotion, paste, spray,aerosol or oil. Carriers that can be used include petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration from about 0.1 to about 15% by weight of the composition,for example from about 0.5 to about 2%.

[0065] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal uses can be in the form of singleplasters, which are suitable for long-term close contact with thepatient's epidermis. Such plasters suitably contain the activeingredient in an aqueous solution, which is buffered where appropriate,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active ingredient concentration is about 1% to about 35%,typically about 3% to about 15%. Another possibility is for the activeingredient to be released by electrotransport or iontophoresis 1 asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986),which is herein incorporated by reference.

[0066] The invention is further directed to a process for preparing thecompounds of the formula (I), which comprises obtaining the compounds ofthe formula (I) by proceeding as shown in the following reaction:

[0067] Compounds of the formula (II) include:

R8-LG (II)

[0068] in which

[0069] R8 is (C₁-C₁₀)-alkylene-COO—(PG-1),(C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-CON—(PG-2)₂,(C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-N-(PG-2)₂, (C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂, or(C₁-C₁₀)-alkylene-B′,

[0070] wherein

[0071] PG-1 is a generally known protective group for esters, such as,for example, (C₁-C₆)-alkyl, benzyl or p-methoxybenzyl, and

[0072] PG-2 is a generally known protective group for amino groups, suchas, for example, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkyloxycarbonyl or(C₆-C₁₂)-aryl-(C₁-C₄)-alkyloxycarbonyl,

[0073] PG-2 replaces either both hydrogens or only one hydrogen atom inthe amino group, and

[0074] B′ is (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene,phenyl, pyrrolyl, imidazolyl, thiazolyi, azetidinyl, thienyl,piperidinyl, pyrrolidinyl, morpholinyl, pyridyl and furyl in whichcycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidinyl,thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl and furyl mayin each case be substituted up to twice by Cl, F, CN, CF₃, OCF₃,COO—(PG-1), COO—(C₁-C₆)-alkyl, CON—(PG-2)₂, CONH—(C₁-C₆)-alkyl,CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, O—(PG-3), or O—(C₁-C₆)-alkyl,

[0075] in which PG-3 is a generally known protective group for alcohols,such as, for example, benzyl, allyl, tetrahydropyranyl ortetrahydrofuranyl, and

[0076] LG is a generally known leaving group such as, for example,halogen, arylsulfonyloxy or alkylsulfonyloxy.

[0077] Compounds of the formula (II) are reacted with anilines of theformula (Ill), which include:

[0078] in which X and PG-2 have the meaning described above, and

[0079] R9, R10, R11, R12 are, independently of one another H, F, Cl, Br,O—(PG-3), CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂-N—(PG-2)₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COO—(PG-1), COO(C₁-C₆)-alkyl,CON—(PG-2)₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,CONH(C₃-C₇)-cycloalkyl, N—(PG-2)₂, NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, it being possiblefor the phenyl ring to be substituted up to twice by F, Cl, CN,O—(PG-3), (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-1), orCOO(C₁-C₆)-alkyl or CON—(PG-2)₂;

[0080] R13 is H, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-COO—(PG-1), or(C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl,

[0081] where PG-1, PG-2 and PG-3 have the meaning described above.

[0082] Compounds of the formula (II) react with compounds of the formula(Ill) in the presence of a base such as, for example, potassium orcesium carbonate, in an organic solvent such as, for example, acetone ordimethylformamide, to give compounds of the formula (IV):

[0083] in which X R8 R9, R10, R11, R12, R13 and PG-2 have the meaningdescribed above, the reaction times are between 2 and 24 hours and thereaction temperature is betweena about 10° C. and the boiling point ofthe solvent used.

[0084] Selective elimination of the protective group PG-2 producescompounds of the formula

[0085] in which X, R8, R9, R10, R11, R12, and R13 have the meaningsstated above. compounds of the formula (V) are reacted with isocyanatesof the formula (VI), which include:

[0086] in which

[0087] A′ is phenyl, or naphthyl, it being possible for the phenyl ornaphthyl radical to be substituted up to three times by F, Cl, Br,O—(PG-3), CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂-N—(PG-2)₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COO—(PG-1),(C₀-C₆)-alkylene-COO(C₁-C₆)-alkyl, CON—(PG-2)₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, (C₀-C₆)-alkylene-N—(PG-2)₂,(C₀-C₆)-alkylene-NH(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, it being possiblefor the phenyl ring to be substituted up to twice by F, Cl, CN,O—(PG-3), (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-1),COO(C₁-C₆)-alkyl or CON—(PG-2)₂,

[0088] where PG-1, PG-2 and PG-3 have the meanings described above.

[0089] The reaction of compounds of formula (V) with isocyanates of theformula (VI) can be carried out in anhydrous organic solvents such as,for example, benzene, toluene or acetonitrile, under a protective gasatmosphere, at reaction temperatures between about 10° C. and theboiling point of the solvent employed, to give compounds of the formula(VII):

[0090] in which X, R8, R9, R10, R11, R12, R13 and A′ have the meaningsdescribed above.

[0091] The compounds of the formula (VII) can, if Ri in compounds of theformula (I) is not a hydrogen atom, be alkylated by reaction withcompounds of the formula (Vil). Compounds of the formula (Vil) include:

R14-LG (VII)

[0092] in which LG has the meaning described above, and

[0093] R14 is H, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-COO—(PG-1),(C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl

[0094] where PG-1 has the meaning described above.

[0095] The reaction of compounds of formula (VII) with compounds offormula (VIII) can be carried out in the presence of a base such as, forexample, 1,8-diazabicyclo[5.4.0]undec-7-ene, in organic solvents suchas, for example, dichloromethane or acetonitrile, to give compounds ofthe formula (IX):

[0096] in which X, R8, R9, R10, R11, R12, R13, R14 and A′ have themeanings described above.

[0097] After elimination, as disclosed in the literature, of allprotective groups, which may be present in the radicals R8, R9, R10,R11, R12, R13, R14, A′ and B′, compounds of the formula (I) areobtained. Conversion of compounds of the formula (I) into their saltstakes place by adding one equivalent of the compound of formula (I) tothe appropriate acid or base in an organic solvent such as, for example,acetonitrile or dioxane or in water and by subsequent removal of thesolvent.

[0098] Another possibility for preparing compounds of the formula (I),in which R2 is a hydrogen atom, is depicted in the following scheme:

[0099] This route entails converting compounds of the formula (V):

[0100] ,in which R2 is a hydrogen atom, and X, R8, R9, R10, R11 and R12have the meanings described above, into isocyanates of the formula (X):

[0101] The reaction between compounds of formula (V) and isocyanates ofthe formula (X) can be carried out by known methods such as, forexample, a reaction with oxalyl chloride in organic solvents such as,for example, 1,2-dichlorethane or dichloromethane, at reactiontemperatures between room temperature and the boiling point of thesolvent.

[0102] Reacting the isocyanates of the formula (X) with amides of theformula (Xl):

[0103] in which A′ has the meaning described above, results in compoundsof the formula (Vll):

[0104] in which R2 is a hydrogen atom, and X, R8, R9, R10, R11 and R12have the meaning described above.

[0105] Compounds of the formula (VII) can, if R1 is not a hydrogen atom,be converted as already described above by alkylation with compounds ofthe formula (VIII) into compounds of the formula (IX), and, ifnecessary, by subsequent elimination of the protective groups intocompounds of the formula (I). Conversion of compounds of the formula (I)into their salts takes place by adding one equivalent of the appropriateacid or base in an organic solvent such as, for example, acetonitrile ordioxane or in water and by subsequent removal of the solvent.

[0106] The examples listed hereinafter serve to illustrate the inventionwithout, however, restricting it. The measured solidification ordecomposition points (m.p.) have not been corrected and generally dependon the heating rate. TABLE 1 Examples

m.p. Ex. A R1 R2 R3 R4 R5 R6 R7 X Salt [° C.] MS* 1 phenyl-2-Cl H H 2-H3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 164 ok 2 phenyl-2-Cl H H 2-H 3-Cl 6-H5-Cl (CH₂)₅—COONa 4-O — 177- ok 179 3 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O bis-2- ok hydroxyethylamine 4 phenyl-2-Cl H H 2-H 3-Cl6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- 163- ok 1-(2-hydroxyethyl)- 1651-hydroxymethyl- propylamine 5 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O lysine 170- ok 172 6 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-HCH₂COOCH₃ 4-S — 168- ok 169 7 phenyl-2,6- H H H H H H CH₂COOCH₃ 4-S —152 ok F₂ 8 phenyl H H H H H H

4-O fumaric acid 182 ok 9 phenyl CH₃ H H H H H

4-O HCl 82 ok 10 phenyl-2-Cl H COCH₃ 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O —137- ok 139 11 phenyl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 189- ok191 12 phenyl-2,4- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 202- ok Cl₂204 13 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅— 4-O — 119- ok COOC₂H₅121 14 phenyl-4- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 188- ok OCH₃190 15 phenyl-3-F H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 210- ok 214 16phenyl-2-F H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 147- ok 151 17phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 149- ok OCH₃ 153 18phenyl-2,3- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 170- ok Cl₂ 172 19phenyl-2-F H H H H H H

4-S — 139-143 20 phenyl-2,6-F₂ H H H H H H

4-S — 162-163 21 phenyl-2,6-F₂ H H 2-H 3-Cl 6-H 5-Cl

4-S — 152 22 phenyl-2-Cl H H H H H H CH₂—COOCH₃ 4-S — 125- 126 23phenyl-3- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — 136 ok OCH₃ 24phenyl-2,4-Cl₂ H H 2-H 3-Cl 6-H 5-Cl

4-O — 189 ok 25 phenyl-3-F H H 2-H 3-Cl 6-H 5-Cl

4-O — 204 ok 26 phenyl-2,3-Cl₂ H H 2-H 3-Cl 6-H 5-Cl

4-O — 182 ok 27 phenyl-3- OCH₃ H H 2-H 3-Cl 6-H 5-Cl

4-O — 176 ok 28 phenyl-2-F H H 2-H 3-Cl 6-H 5-Cl

4-O — 144 ok 29 phenyl H H 2-H 3-Cl 6-H 5-Cl

4-O — 204 ok 30 phenyl-4- OCH₃ H H 2-H 3-Cl 6-H 5-Cl

4-O TFA ok 31 phenyl-2- OCH₃ H H 2-H 3-Cl 6-H 5-Cl

4-O TFA ok 32 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₃—COOH 4-O — ok 33phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₄—COOH 4-O — ok 34 phenyl-2-Cl HH 2-H 3-Cl 6-H 5-Cl (CH₂)₆—COOH 4-O — ok 35 phenyl-2-Cl H H 2-H 3-Cl 6-H5-Cl (CH₂)₇—COOH 4-O — ok 36 phenyl-2-Cl CH₃ H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O — ok 37 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₃—COOH4-O 3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 38phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₄—COOH 4-O 3-hydroxy- ok1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 39 phenyl-2-Cl H H 2-H3-Cl 6-H 5-Cl (CH₂)₆—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 40 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl(CH₂)₇—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl-propylamine 41 phenyl-2,4-Cl₂ H H 2-H 3-Cl 6-H 5-Cl (CH₂)₃—COOH 4-O3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 42phenyl-2,4-Cl₂ H H 2-H 3-Cl 6-H 5-Cl (CH₂)₄—COOH 4-O 3-hydroxy- ok1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 43 phenyl-2,4-Cl₂ H H2-H 3-Cl 6-H 5-Cl (CH₂)₆—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 44 phenyl-2,4-Cl₂ H H 2-H 3-Cl 6-H 5-Cl(CH₂)₇—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl-propylamine 45 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 46 phenyl-2,4- Cl₂ H H 2-H 3-Cl 6-H 5-Cl

4-O HCl 182 ok 47 phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O3-hydroxy- ok CH₃ 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 48phenyl-4- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- ok CH₃1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 49 phenyl-3- H H 2-H3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- ok CH₃ 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 50 phenyl-4-F H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl-propylamine 51 phenyl-3-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 52phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOK 4-O — ok 53 phenyl-4-Br HH 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 54 phenyl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH4-O 3-hydroxy- 172 ok 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine55 phenyl-3-F H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- 170 ok1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 56 phenyl-2- H H 2-H3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O 3-hydroxy- 119 ok OCH₃ 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 57 phenyl-2,3- H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O 3-hydroxy- 160 ok Cl₂ 1-(2-hydroxyethyl)-1-hydroxymethyl- propylamine 58 phenyl-4-Cl H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O 3-hydroxy- ok 1-(2-hydroxyethyl)- 1-hydroxymethyl-propylamine 59 phenyl-2,4- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O3-hydroxy- ok Cl₂ 1-(2-hydroxyethyl)- 1-hydroxymethyl- propylamine 60phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₃—COOH 4-O — 207 ok CH₃ 61phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₄—COOH 4-O — 167 ok CH₃ 62phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₆—COOH 4-O — 185 ok CH₃ 63phenyl-2- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₇—COOH 4-O — 153 ok CH₃ 64phenyl-2,4- H H 2-H 3-F 6-H 5-H (CH₂)₃—COOH 4-O — ok Cl₂ 65 phenyl-2,4-H H 2-H 3-F 6-H 5-H (CH₂)₄—COOH 4-O — ok Cl₂ 66 phenyl-2,4- H H 2-H 3-F6-H 5-H (CH₂)₅—COOH 4-O — ok Cl₂ 67 phenyl-2,4- H H 2-H 3-F 6-H 5-H(CH₂)₆—COOH 4-O — ok Cl₂ 68 phenyl-2,4- H H 2-H 3-F 6-H 5-H (CH₂)₇—COOH4-O — ok Cl₂ 69 phenyl-2,4- H H 2-CH₃ 4-H 6-H 5-H (CH₂)₃—COOH 3-O — okCl₂ 70 phenyl-2,4- H H 2-CH₃ 4-H 6-H 5-H (CH₂)₄—COOH 3-O — ok Cl₂ 71phenyl-2,4- H H 2-CH₃ 4-H 6-H 5-H (CH₂)₅—COOH 3-O — ok Cl₂ 72phenyl-2,4- H H 2-CH₃ 4-H 6-H 5-H (CH₂)₆—COOH 3-O — ok Cl₂ 73phenyl-2,4- H H 2-CH₃ 4-H 6-H 5-H (CH₂)₇—COOH 3-O — ok Cl₂ 74phenyl-2,4- H H 2-CH₃ 3-H 6-H 5-H (CH₂)₃—COOH 4-O — ok Cl₂ 75phenyl-2,4- H H 2-CH₃ 3-H 6-H 5-H (CH₂)₄—COOH 4-O — ok Cl₂ 76phenyl-2,4- H H 2-CH₃ 3-H 6-H 5-H (CH₂)₅—COOH 4-O — ok Cl₂ 77phenyl-2,4- H H 2-CH₃ 3-H 6-H 5-H (CH₂)₆—COOH 4-O — ok Cl₂ 78phenyl-2,4- H H 2-CH₃ 3-H 6-H 5-H (CH₂)₇—COOH 4-O — ok Cl₂ 79phenyl-2,4- H H 2-H 3-CH₃ 6-H 5-CH₃ (CH₂)₃—COOH 4-O — ok Cl₂ 80phenyl-2,4- H H 2-H 3-CH₃ 6-H 5-CH₃ (CH₂)₄—COOH 4-O — ok Cl₂ 81phenyl-2,4- H H 2-H 3-CH₃ 6-H 5-CH₃ (CH₂)₅—COOH 4-O — ok Cl₂ 82phenyl-2,4- H H 2-H 3-CH₃ 6-H 5-CH₃ (CH₂)₆—COOH 4-O — ok Cl₂ 83phenyl-2,4- H H 2-H 3-CH₃ 6-H 5-CH₃ (CH₂)₇—COOH 4-O — ok Cl₂ 84phenyl-2,4- H H H H H H (CH₂)₃—COOH 3-O — ok Cl₂ 85 phenyl-2,4- H H H HH H (CH₂)₄—COOH 3-O — ok Cl₂ 86 phenyl-2,4- H H H H H H (CH₂)₅—COOH 3-O— ok Cl₂ 87 phenyl-2,4- H H H H H H (CH₂)₇—COOH 3-O — ok Cl₂ 88phenyl-2,4- H H H H H H (CH₂)₃—COOH 4-O — ok Cl₂ 89 phenyl-2,4- H H H HH H (CH₂)₄—COOH 4-O — ok Cl₂ 90 phenyl-2,4- H H H H H H (CH₂)₅—COOH 4-O— ok Cl₂ 91 phenyl-2,4- H H H H H H (CH₂)₆—COOH 4-O — ok Cl₂ 92phenyl-2,4- H H H H H H (CH₂)₇—COOH 4-O — ok Cl₂ 93 phenyl-3,4- H H 2-H3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok Cl₂ 94 phenyl-2,4- Cl₂ H H 2-H 3-Cl6-H 5-Cl

4-O HCl ok 95 phenyl-3-F H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 96 phenyl-2,3- Cl₂ H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 97 phenyl-3- OCH₃ H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 98 phenyl-2-F H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 99 phenyl H H 2-H 3-Cl 6-H 5-Cl

4-O HCl ok 100 phenyl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok3-SO₂CH₃ 101 phenyl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 2-SO₂CH₃102 phenyl-2-Cl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 4-SO₂CH₃ 103phenyl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 2,4-(CH₃)₂ 104phenyl-4-Cl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 2-F 105phenyl-2-Cl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 4-F 106 phenyl-H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 4-COOCH₃ 107 phenyl- H H 2-H3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 4-SO₂CH₃ 108 phenyl-2-Cl H H 2-H 3-Cl6-H 5-Cl

4-O — ok 109 phenyl-4-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok2-CH₃ 110 phenyl-3-F- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 4-NO₂111 phenyl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 2-COOCH₃ 112phenyl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 3-COOCH₃- 5-NO₂ 113phenyl-3-CF₃ H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 114phenyl-2,4-Cl₂ H H H H H H (CH₂)₆—COOH 3-O — ok 115 phenyl-2,4-Cl₂ H H2-H 3-Cl 6-H 5-H (CH₂)₄—COOH 4-O — ok 116 phenyl-2,4-Cl₂ H H 2-F 3-H 6-H5-H (CH₂)₅—COOH 4-O — ok 117 phenyl-4-CF₃ H H 2-H 3-Cl 6-H 5-Cl(CH₂)₅—COOH 4-O — ok 118 phenyl-2-Cl H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—CONH₂4-O — ok 119 phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-CH₃ 5-H (CH₂)₄—COOH 4-O — ok120 phenyl-2,4-Cl₂ H H 2-H 4-CH₃ 6-H 5-H (CH₂)₄—COOH 3-O — ok 121phenyl-2,4-Cl₂ H H 2-H 4-OCH₃ 6-H 5-H (CH₂)₄—COOH 3-O — ok 122phenyl-2,4-Cl₂ H H 2-H 3-COOCH₃ 6-H 5-H (CH₂)₄—COOH 4-O — ok 123phenyl-2,4-Cl₂ H H 2-Cl 3-H 6-H 5-H (CH₂)₄—COOH 4-O — ok 124phenyl-2,4-Cl₂ H H 2-H 3-cHexyl 6-H 5-H (CH₂)₄—COOH 4-O — ok 125phenyl-2,4-Cl₂ H H 2-CH₃ 3-CH₃ 6-H 5-H (CH₂)₄—COOH 4-O — ok 126phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-CH₃ 5-H (CH₂)₅—COOH 4-O — ok 127phenyl-2,4-Cl₂ H H 2-H 4-CH₃ 6-H 5-H (CH₂)₅—COOH 3-O — ok 128phenyl-2,4-Cl₂ H H 2-H 4-OCH₃ 6-H 5-H (CH₂)₅—COOH 3-O — ok 129phenyl-2,4-Cl₂ H H 2-H 3-COOCH₃ 6-H 5-H (CH₂)₅—COOH 4-O — ok 130phenyl-2,4-Cl₂ H H 2-Cl 3-H 6-H 5-H (CH₂)₅—COOH 4-O — ok 131phenyl-2,4-Cl₂ H H 2-H 3-cHexyl 6-H 5-H (CH₂)₅—COOH 4-O — ok 132phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-H 5-CH₃ (CH₂)₅—COOH 4-O — ok 133phenyl-2,4-Cl₂ H H 2-CH₃ 3-CH₃ 6-H 5-H (CH₂)₅—COOH 4-O — ok 134phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-CH₃ 5-H (CH₂)₇—COOH 4-O — ok 135phenyl-2,4-Cl₂ H H 2-H 4-CH₃ 6-H 5-H (CH₂)₇—COOH 3-O — ok 136phenyl-2,4-Cl₂ H H 2-H 4-OCH₃ 6-H 5-H (CH₂)₇—COOH 3-O — ok 137phenyl-2,4-Cl₂ H H 2-H 3-COOCH₃ 6-H 5-H (CH₂)₇—COOH 4-O — ok 138phenyl-2,4-Cl₂ H H 2-Cl 3-H 6-H 5-H (CH₂)₇—COOH 4-O — ok 139phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-H 5-CH₃ (CH₂)₇—COOH 4-O — ok 140phenyl-2,4-Cl₂ H H 2-CH₃ 3-CH₃ 6-H 5-H (CH₂)₇—COOH 4-O — ok 141phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-CH₃ 5-H (CH₂)₃—COOH 4-O — ok 142phenyl-2,4-Cl₂ H H 2-H 4-CH₃ 6-H 5-H (CH₂)₃—COOH 3-O — ok 143phenyl-2,4-Cl₂ H H 2-H 4-OCH₃ 6-H 5-H (CH₂)₃—COOH 3-O — ok 144phenyl-2,4-Cl₂ H H 2-H 3-COOCH₃ 6-H 5-H (CH₂)₃—COOH 4-O — ok 145phenyl-2,4-Cl₂ H H 2-Cl 3-H 6-H 5-H (CH₂)₃—COOH 4-O — ok 146phenyl-2,4-Cl₂ H H 2-H 3-cHexyl 6-H 5-H (CH₂)₃—COOH 4-O — ok 147phenyl-2,4-Cl₂ H H 2-CH₃ 3-H 6-H 5-CH₃ (CH₂)₃—COOH 4-O — ok 148phenyl-2,4-Cl₂ H H 2-CH₃ 3-CH₃ 6-H 5-H (CH₂)₃—COOH 4-O — ok 149phenyl-2,6-Cl₂ H H 2-H 3-Cl 6-H 5-Cl (CH₂)₅—COOH 4-O — ok 150phenyl-6-Cl- H H 2-H 3-Cl 6-H 5-Cl (CH₂)₃—COOH 4-O — ok 3-COOH 151phenyl-2,4-Cl₂ H H 2-CH₃ 4-H 6-H 5-H (CH₂)₄—COOH 3-O bis-2- okhydroxyethlamine 152 phenyl-2,4-Cl₂ H H 2-Cl 3-H 6-H 5-H (CH₂)₃—COOH 4-Obis-2- ok hydroxyethlamine

[0107] The compounds of the formula (I) are distinguished by beneficialeffects on glucose metabolism; for example, they lower the blood glucoselevel and are suitable for treating type II diabetes. The compounds canbe employed alone or in combination with other blood glucose-loweringactive ingredients. Examples of such other blood glucose-lowering activeingredients are sulfonylureas (such as, for example, glimerpiride,glibenclamide), glitazones (such as, for example, troglitazone,rosiglitazone), alpha-glucosidase inhibitors (such as, for example,acarbose, miglitol) or insulins.

[0108] The activity of the compounds was assayed as follows:

[0109] Glycogen Phosphorylase a Activity Assay

[0110] The effect of compounds on the activity of the active form ofglycogen phosphorylase (GPa) was measured in the reverse direction byfollowing the synthesis of glycogen from glucose 1-phosphate bydetermining the liberation of inorganic phosphate. All the reactionswere carried out as duplicate determinations in microtiter plates with96 wells (Half Area Plates, Costar No 3696), measuring the change inabsorption owing to the formation of the reaction product at thewavelength specified hereinafter in a Multiskan Ascent Elisa Reader (LabSystems, Finland).

[0111] In order to measure the GPa enzymic activity in the reversedirection, the general method of Engers et al. (Engers H D, Shechosky S,Madsen N B, Can J Biochem 1970 Jul;48(7):746-754) was used to measurethe conversion of glucose 1-phosphate into glycogen and inorganicphosphate. However, the following modifications to Engers method wereobserved: human glycogen phosphorylase a (for example with about 0.76 mgof protein/ml (Aventis Pharma Deutschland GmbH), was dissolved in buffersolution E (25-mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mMdithiothreitol) and was diluted with buffer T (50 mM hepes, pH 7.0, 100mM KCl, 2.5 mM EDTA, 2.5 mM MgCl₂·6H₂O) and addition of 5 mg/ml glycogento a concentration of 10 μg of protein/ml. Test substances were preparedas 10 mM solutions in DMSO and diluted to 50 μM with buffer solution T.10 μl of this solution were mixed with 10 μl of 37.5 mM glucose(dissolved in buffer solution T and 5 mg/ml glycogen), 10 μl of asolution of human glycogen phosphorylase a (10 pg of protein/ml), and 20μl of glucose 1-phosphate, 2,5 g mM. The baseline glycogen phosphorylasea activity in the absence of test substance was determined by adding 10μl of buffer solution T (0.1% DMSO). The mixture was incubated at roomtemperature for 40 minutes, and the liberated organic phosphate wasmeasured by the general method of Drueckes et al. (Drueckes P, SchinzelR, Palm D, Anal Biochem 1995 Sep 1;230(1):173-177) with the followingmodifications: 50 μl of a stop solution containing 7.3 mM ammoniummolybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, and 0.9% SDS areadded to 50 μl of the enzyme mixture. After incubation at 45° C. for 60minutes, the absorption at 820 nm was measured. In order to determinethe background absorption, in a separate mixture, the stop solution wasadded immediately after addition of the glucose 1-phosphate solution.This test was carried out with a concentration of 10 μM of the testsubstance in order to determine the particular inhibition of glycogenphosphorylase a in vitro by the test subtance.

[0112] Table 2: Biological Activity: % inhibition at Ex. 10 μM 1 87 2 733 75 4 79 5 77 12 92 20 35 29 78 30 76 31 86 41 50 44 11 46 36 47 46 4913 51 36 53 22 90 34 100 78 101 93 102 14 106 35 111 88 112 100 116 100117 99 118 70 119 97 120 40 122 12 128 95 147 88 149 76

[0113] It is evident from the table that the compounds of the formula(I) inhibit the activity of glycogen phosphorylase a and thus are verysuitable for lowering the blood glucose level.

[0114] The preparation of some examples is described in detail below,and the other compounds of the formula (I) were obtained analogously:

[0115] Experimental part:

EXAMPLE 1

[0116] 6-{2,6-Dichloro-4-[(2-chlorobenzoyl)ureido]phenoxy}hexanoic acid

[0117] a) Ethyl 6-(4-acetylamino-2,6-dichlorophenoxy)hexanoate

[0118] 13.3 ml (74.9mmol) of ethyl 6-bromohexanoate and 52.1 g (160mmol) of cesium carbonate were added to a solution of 15.0 g (68.1 mmol)of N—(3,5-dichloro-4-hydroxyphenyl)acetamide in 300 ml of acetone. Thesuspension was boiled under reflux for 8 hours, and then 600 ml of waterwere added. The mixture was extracted twice with 400 ml ofdichloromethane and with 400 ml of MTB ether each time. The combinedorganic phases were washed with water and concentrated in a rotaryevaporator. The product was employed in the next step withoutpurification. Crude yield was 30 g.

[0119] b) 6-(4-Acetylamino-2,6-dichlorophenoxy)hexanoic acid

[0120] 30 g of crude material from step a) were mixed with 800 ml of 1 Mpotassium hydroxide solution and stirred at room temperature for 3 days,after which 600 ml of water were added and the pH was adjusted to 5.5with about 80 ml of glacial acetic acid. The precipitated product wasfiltered off with suction and washed twice with 40 ml of water eachtime. The precipitate was dried under high vacuum and produced 14.6 g ofthe required compound.

[0121] c) 6-(4-Amino-2,6-dichlorophenoxy)hexanoic acid

[0122] 7.5 g (22.4 mmol) of6-(4-acetylamino-2,6-dichlorophenoxy)hexanoic acid in 140 ml of 1 mpotassium hydroxide solution in methanol/water (3:1) were boiled underreflux overnight. The methanol was removed in a rotary evaporator, andthe residue was diluted with about 30 ml of water and acidified to pH 5with glacial acetic acid. The mixture was stirred in an ice bath for 30minutes and then filtered with suction. The crude product was subjectedto column chromatography using n-heptane/ethyl acetate =1/1 and produced4.3 g (14.7 mmol, 66%) of the required product.

[0123] d) 6-{2,6-Dichloro-4-[(2-chlorobenzoyl)ureido]phenoxy}hexanoicacid

[0124] A solution of 7.5 g (41.1 mmol) of 2-chlorobenzoyl isocyanate in300 ml of acetonitrile was added to a suspension of 10.0 g (34.2 mmol)of 6-(4-amino-2,6-dichlorophenoxy)hexanoic acid in 700 ml of dryacetonitrile under a protective gas atmosphere at room temperature. Themixture was boiled under reflux for 2 hours and cooled to roomtemperature. The resulting precipitate was filtered off with suction andwashed with 50 ml of acetonitrile. The residue was stirred with 100 mlof methanol, filtered off with suction, washed with a little methanoland dried at 40° C. under vacuum overnight. 13.7 g (28.9 mmol, 85%) ofthe required product were obtained. Melting point: about 171-173° C.

We claim:
 1. A compound of the formula (I)

wherein A is phenyl, or naphthyl, wherein the phenyl or naphthyl radicalis optionally substituted up to three times by one or more of thefollowing radicals: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO(C₁-C₇)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-Alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenylring in NH—CO-phenyl, or NH—SO₂-phenyl is optionally substituted up totwice by one or two of the following radicals: F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl, orCONH₂; R1, R2 are, independently of one another: H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl; R3, R4,R5, R6 are, independently of one another: H, F, Cl, Br, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl,S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyi]₂, CONH(C₃-C₇)-cycloalkyl, N H₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl,or NH—SO₂-phenyl, wherein the phenyl ring in NH—CO-phenyl, orNH—SO₂-phenyl is optionally substituted up to twice by one or two of thefollowing radicals: F, Cl, CN, OH, (C₁-C₆)-Alkyl, O—(C₁-C₆)-alkyl, CF₃,OCF₃, COOH, COO(C₁-C₆)-alkyl, or CONH₂; X is O or S; R7 is(C₁-C₁₀)-alkylene-COOH, (C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CONH₂, (C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B; wherein B is (C₃-C₇)-cycloalkyl, pyrrolyl,imidazolyl, thiazolyl, azetidinyl, thienyl, piperidinyl, pyrrolidinyl,morpholinyl, pyridyl-methyl, orfuryl, wherein cycloalkyl, phenyl,pyrrolyl, imidazolyl, thiazolyl, azetidinyl, thienylmethyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl or furyl may in each case beoptionally substituted up to twice by one or two of the followingradicals: Cl, F, CN, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, CONH₂,CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, OH, orO—(C₁-C₆)-alkyl; or a physiologically tolerated salt thereof, except thecompounds of the formula

and except compounds of the formula (I) in which the radicals are, atthe same time: A phenyl; X O; R1 H; R7 —(C₁-C₄)-alkyl-B; B(C₃-C₇)-cycloalkyl, or heteroaryl.
 2. The compound of the formula I asclaimed in claim 1, wherein A is phenyl, or naphthyl, wherein the phenylor naphthyl radical are optionally substituted up to three times by oneor more of the following radicals: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl, S—(ClC₆)-alkyl,S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene -COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenylring in NH—CO-phenyl, or NH—SO₂-phenyl is optionally substituted up totwice by one or two of the following radicals: F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl orCONH₂; R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl; R3, R4,R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF₃, NO₂,CN, OCF_(3, O—(C) ₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl,S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl,or NH—SO₂-phenyl, wherein the phenyl ring in NH—CO-phenyl, orNH—SO₂-phenyl is optionally substituted up to twice by one or two of thefollowing radicals: F, Cl, CN, OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃,OCF₃, COOH, COO(C₁-C₆)-alkyl or CONH₂; X is O or S; R7 is(C₁-C₁₀)-alkylene-COOH, (C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CONH₂, (C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B; wherein B is (C₃-C₇)-cycloalkyl, pyrrolyl,imidazolyl, thiazolyl, azetidinyl, thienyl-methyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl-methyl or furyl, wherein cycloalkyl,phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidinyl, thienyl,piperidinyl, pyrrolidinyl, morpholinyl, pyridyl or furyl may in eachcase be optionally substituted up to twice by one or two of thefollowing radicals: Cl, F, CN, CF_(3, OCF) ₃, COOH, COO—(C₁-C₆)-alkyl,CONH2, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, OH, orO—(C₁-C₆)-alkyl; or a physiologically tolerated salt thereof, except thecompounds of the formula

and except the compounds of the formula I in which the radicals are, atthe same time: A phenyl; X O; R1 H; R7 —(C₁-C₄)-alkyl-B; B(C₃-C₇)-cycloalkyl, or heteroaryl.
 3. The compound of the formula I asclaimed in claim 1, wherein A is phenyl, wherein the phenyl radical isoptionally substituted up to twice by one or two of the followingradicals: F, Cl, Br, O—(C₁-C₆)-alkyl; R1, R2 are, independently of oneanother, H, (C₁-C₆)-alkyl, or CO—(C₁-C₆)-alkyl; R3, R4, R5, R6 are,independently of one another, H, Cl, F, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl,—COO—(C₁-C₆)-alkyl; X is O; R7 is (C₁-C₁₀)-alkylene-COOH,(C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl, or (C₁-C₁o)-alkylene-CONH₂; or aphysiologically tolerated salt thereof, except the compounds of theformula


4. A pharmaceutical composition comprising one or more of the compoundsof claim 1 and a pharmaceutically acceptable carrier.
 5. Apharmaceutical composition comprising one or more of the compounds ofclaim 1 and one or more blood glucose-lowering active ingredients.
 6. Amethod for lowering blood glucose, comprising administering to a patientin need thereof an effective amount of at least one compound of claim 1.7. The method according to claim 6, further comprising administering atleast one other blood glucose-lowering active ingredient.
 8. A methodfor treating type II diabetes, comprising administering to a patient inneed thereof an effective amount of at least one compound of claim
 1. 9.A process for producing a pharmaceutical composition, comprising mixingone or more of the compounds of claim 1 with a pharmaceuticallyacceptable carrier, and converting this mixture into a form suitable foradministration.
 10. A method for lowering blood glucose, comprisingadministering to a patient in need thereof an effective amount of atleast one compound of the formula (I):

or a physiologically tolerated salt thereof, wherein A is phenyl, ornaphthyl, wherein the phenyl or naphthyl radical is optionallysubstituted up to three times by one or more of the following radicals:F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO (C₁-C₇)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-Alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenylring in NH—CO-phenyl, or NH—SO₂-phenyl is optionally substituted up totwice by one or two of the following radicals: F, Cl, CN, OH,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO(C₁-C₆)-alkyl, orCONH₂; R1, R2 are, independently of one another: H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COOH, or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl; R3, R4,R5, R6 are, independently of one another: H, F, Cl, Br, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl,S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl,or NH—SO₂-phenyl, wherein the phenyl ring in NH—CO-phenyl, orNH—SO₂-phenyl is optionally substituted up to twice by one or two of thefollowing radicals: F, Cl, CN, OH, (C₁-C₆)-Alkyl, O—(C₁-C₆)-alkyl, CF₃,OCF₃, COOH, COO(C₁-C₆)-alkyl, or CONH₂; X is O or S; R7 is(C₁-C₁₀)-alkylene-COOH, (C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl,(C₁-C₁₀)-(C₁-C₁₀)-alkylene-COH₂, (C₁-C₁₀)-alkylene-CONH-(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-NH₂,(C₁-C₁₀-alkylene-NH (C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B; wherein B is (C₃-C₇)-cycloalkyl, pyrrolyl,imidazolyl, thiazolyl, azetidinyl, thienyl, piperidinyl, pyrrolidinyl,morpholinyl, pyridyl-methyl, or furyl, wherein cycloalkyl, phenyl,pyrrolyl, imidazolyl, thiazolyl, azetidinyl, thienylmethyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl or furyl may in each case beoptionally substituted up to twice by one or two of the followingradicals: Cl, F, CN, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, CONH₂,CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, OH, orO—(C₁-C₆)-alkyl.
 11. A process for preparing a compound of claim 1,according to the following diagram:

wherein the compounds of formula (Il): R8-LG (II) in which R8 is(C₁-C₁₀)-alkylene-COO—(PG-1), (C₆-C₁₀)-alkylene-COO—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—(PG-2)₂, (C₁-C₁₀)-alkylene-CONH—(C₁-C₆)-alkyl,(C₁-C₁₀)-alkylene-CON—[(C₁-C₆)-alkyl]₂, (C₁-C₁₀)-alkylene-N—(PG-2)₂,(C₁-C₁₀)-alkylene-NH(C₁-C₆)-alkyl, (C₁-C₁₀)-alkylene-N[(C₁-C₆)-alkyl]₂,or (C₁-C₁₀)-alkylene-B′, PG-1 is a protective group for esters, PG-2 isa protective group for amino groups, which replaces either bothhydrogens or only one hydrogen atom in the amino group, B′ is(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, phenyl,pyrrolyl, imidazolyl, thiazolyl, azetidinyl, thienyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl and furyl wherein cycloalkyl, phenyl,pyrrolyl, imidazolyl, thiazolyl, azetidinyl, thienyl, piperidinyl,pyrrolidinyl, morpholinyl, pyridyl and furyl may, in each case, beoptionally substituted up to twice by one or two of the followingradicals: Cl, F, CN, CF₃, OCF₃, COO—(PG-1), COO—(C₁-C₆)-alkyl,CON—(PG-2)₂, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl,O—(PG-3), O—(C₁-C₆)-alkyl, PG-3 is a protective group for alcohols, andLG is a leaving group, is reacted with anilines of the formula (III):

wherein X has the meaning as in claim 1 and PG-2 has the meaningdescribed above, and wherein R9, R10, Rh1, R12 are, independently of oneanother: H, F, Cl, Br, O—(PG-3), CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl, O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₁-C₆)-alkenyl, S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂-(C₁-C₆)-alkyl, SO₂-N—(PG-2)₂, (C₁-C₆)-alkyl, (C₁-C₆)-alkenyl,(C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COO—(PG-1), COO(C₁-C₆)-alkyl,CON—(PG-2)₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,CONH(C₃-C₇)-cycloalkyl, N—(PG-2)₂, NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenylring in NH—CO-phenyl, or NH—SO₂-phenyl, is optionally substituted up totwice by one or two of the following radicals: F, Cl, CN, O—(PG-3),(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-1), COO(C₁-C₆)-alkylor CON—(PG-2)₂, R13 is H, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl,CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-COO—(PG-1), or(C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl, and wherein PG-1, PG-2 and PG-3 havethe meaning described above, to give compounds of the formula (IV):

wherein X, R8, R9, R10, R11, R12, R13 and PG-2 have the meaningdescribed above; selectively eliminating the protective group PG-2 toproduce compounds of the formula (V):

wherein X, R8, R9, R10, R11, R12, and R13 have the meanings statedabove; reacting compounds of the formula (V) with isocyanates of theformula (VI):

wherein A′ is phenyl, or naphthyl, and wherein the phenyl or naphthylradical is optionally substituted up to three times by F, Cl, Br,O—(PG-3), CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl,O—(C₁-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkenyl,S—(C₁-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂-(C₁-C₆)-alkyl, SO₂—N—(PG-2)₂,(C₁-C₆)-alkyl, (C₁-C₆)-alkenyl, (C₁-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COO—(PG-1),(C₀-C₆)-alkylene-COO(C₁-C₆)-alkyl, CON—(PG-2)₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, CONH(C₃-C₇)-cycloalkyl, (C₀-C₆)-alkylene-N—(PG-2)₂,(C₀-C₆)-alkylene-NH(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-N[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenylring in NH—CO-phenyl, or NH—SO₂-pheny is optionally substituted up totwice by one or two of the following radicals: F, Cl, CN, O—(PG-3),(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-1), COO(C₁-C₆)-alkylor CON—(PG-2)₂, and PG-1, PG-2 and PG-3 have the meaning describedabove, to give compounds of the formula (VIlI):

wherein X, R8, R9, R10, R1 1, R12, Ri 3 and A′ have the meaningsdescribed above; alkylating the compounds of the formula (VIl), if R1 incompounds of the formula (I) is not a hydrogen atom, with compounds ofthe formula (Vil): R14-LG (VIII) wherein R14 is H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-COO—(PG-1), or (C₁-C₆)-alkylene-COO—(C₁-C₆)-alkyl,wherein LG and PG-1 have the meanings described above, to give compoundsof formula (IX):

wherein X, R8, R9, R10, R 1I, Ri 2, R13, R14 and A′ have the meaningsdescribed above, optionally eliminating the protective groups that arepresent in the radicals R8, R9, R10, R1h, R12, R13, R14, A′ and B′ togive compounds of the formula (I), and optionally converting thecompounds of the formula (I) into their salts.
 12. The process accordingto claim 11, wherein PG-1 is (C₁-C₆)-alkyl, benzyl or p-methoxybenzyl.13. The process according to claim 11, wherein PG-2 is(C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkyloxycarbonyl or (C₆-CI₂)-aryl-(C₁-C₄)-al kyloxycarbonyl.
 14. The process according to claim11, wherein PG-3 is benzyl, allyl, tetrahydropyranyl ortetrahydrofuranyl.
 15. The process according to claim 11, wherein LG ishalogen, arylsulfonyloxy or alkylsulfonyloxy.
 16. The process accordingto claim 11, wherein the reaction of compounds of formula (II) withcompounds of formula (III) is carried out in the presence of potassiumor cesium carbonate.
 17. The process according to claim 11, wherein thereaction of compounds of formula (II) with compounds of formula (III) iscarried out in acetone or dimethylformamide.
 18. The process accordingto claim 11, wherein the alkylation of compounds of formula (VII) withcompounds of formula (VIII) is carried out in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene.